This application addresses broad Challenge Area (15): Translational Science and specific Challenge Topic, 15-DK-106: Translating Basic Hematology Concepts. The proposal involves the application of a novel assay for the iron metabolism hormone hepcidin in the approach to prevent, diagnose, and treat iron deficiency in infants. Iron deficiency anemia (IDA) affects nearly 3% of children in the U.S. aged 1-2 years. At least 9% more are non-anemic, but iron deficient (ID) and are at risk for neurodevelopmental deficits. Although the specific recommendations vary, Federal agencies and professional practice associations uniformly suggest that pediatricians screen infants for ID, typically before the end of the first year of life. The method of screening also varies, but, in each case, a compromise is made between the rapidity, invasiveness, cost, sensitivity, and specificity of the test. Not surprisingly, the most sensitive test, the cellular hemoglobin of the reticulocytes (CHr), is the most invasive and most costly, and, furthermore, is not available on all automated hematology instruments. Conversely, the least costly, least invasive test, the finger stick hemoglobin, is also the least sensitive. Furthermore, many ID screening tests do not directly interrogate the iron status of the child. Because of the ease of correcting ID with dietary supplements and the imperative to identify an early ID (EID) state before anemia develops, when children are nonetheless at risk for neurological sequelae, there exists a compelling need to identify a sensitive, cost-effective, rapid, minimally invasive screen for EID. This proposal will evaluate a new test, the serum hepcidin, as a screen for ID in infants. Furthermore, using the same dataset, we will address the possibility that variants in the gene encoding TMPRSS6, a protein that modulates hepcidin production, could predispose children to a form of ID in infancy that may not be best treated with oral iron supplements. Hepcidin is a peptide hormone produced in the liver largely in response to iron stores. Hepcidin is the central regulator of systemic iron metabolism. Hepcidin negatively regulates the egress of iron from cells, particularly duodenal intestinal epithelial cells, where iron is absorbed into the body, and macrophages, which recycle iron from effete RBCs. Thus, the appropriate physiological response to ID is to decrease hepcidin production to promote iron absorption from the intestine and release stored iron from macrophages. Serum hepcidin levels can now be measured with a sensitive enzyme-linked immunosorbent assay (ELISA). Initial studies have shown that hepcidin is markedly decreased or not detectable in the serum of iron deficient adults. Furthermore, there is a direct relationship between serum hepcidin and serum ferritin, the latter of which has been shown to correlate with iron stores. By evaluating the relationship of serum hepcidin to iron stores specifically in the infant population uniquely at risk for ID and ID-associated complications we should be able to determine the potential superiority or inferiority of this test in comparison to all other ID screening methodologies. Genetic defects that lead to abnormally low levels of hepdicin production in response to body iron stores underlie the vast majority of cases of the hereditary iron overload disorders collectively termed hereditary hemochromatosis. Recently, we identified biallelic mutations in the liver-specific transmembrane serine protease, TMPRSS6, in individuals with the phenotype opposite to hereditary hemochromatosis-a disorder termed iron refractory ID anemia (IRIDA). IRIDA patients have ID that is unresponsive to oral and parenteral iron supplementation due to inappropriately increased hepcidin expression. Furthermore, we have now determined that individuals heterozygous for TMPRSS6 mutations have mildly inappropriately elevated hepcidin levels. Several common and many low frequency amino acid variants (cSNPs) exist in TMPRSS6 in the human population. Here, we propose to determine if there is a relationship between these cSNPs in TMPRSS6 and the risk for ID in infancy. This is potentially important as it could identify those individuals at greatest risk for ID in this period and might dictate that they be treated presumptively or differently than those with "common" ID. We anticipate that these data will 1) determine if hepcidin is of potential clinical value for routine evaluation of ID in the infant population, and 2) whether TMPRSS6 variants are a risk factor for infantile ID. Ultimately, if our hypotheses are correct, this study will lay the foundation for better screening and management of ID, not only in this population, but in all children and adults alike. Iron deficiency is common in infancy and can lead to anemia as well as developmental delays. Consequently, it is recommended that all children be screened for iron deficiency in infancy. Here, in order to improve preventative care for children, we will test the utility of a new, potentially more accurate blood screening test for iron deficiency and begin to determine if there is a genetic susceptibility to iron deficiency in infancy. PUBLIC HEALTH RELEVANCE: Iron deficiency is common in infancy and can lead to anemia as well as developmental delays. Consequently, it is recommended that all children be screened for iron deficiency in infancy. Here, in order to improve preventative care for children, we will test the utility of a new, potentially more accurate blood screening test for iron deficiency and begin to determine if there is a genetic susceptibility to iron deficiency in infancy.